EP3224245B1 - Nekroseinhibitoren - Google Patents

Nekroseinhibitoren Download PDF

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Publication number
EP3224245B1
EP3224245B1 EP15871955.9A EP15871955A EP3224245B1 EP 3224245 B1 EP3224245 B1 EP 3224245B1 EP 15871955 A EP15871955 A EP 15871955A EP 3224245 B1 EP3224245 B1 EP 3224245B1
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Prior art keywords
compound
unsubstituted
substituted
corresponding sulfonamide
cdcl
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EP15871955.9A
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English (en)
French (fr)
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EP3224245A1 (de
EP3224245A4 (de
Inventor
Zhiyuan Zhang
Xiaodong Wang
Yaning SU
Hanying RUAN
Yan Ren
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National Institute of Biological Sciences Beijin
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National Institute of Biological Sciences Beijin
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/82—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
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    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01C—MEASURING DISTANCES, LEVELS OR BEARINGS; SURVEYING; NAVIGATION; GYROSCOPIC INSTRUMENTS; PHOTOGRAMMETRY OR VIDEOGRAMMETRY
    • G01C19/00—Gyroscopes; Turn-sensitive devices using vibrating masses; Turn-sensitive devices without moving masses; Measuring angular rate using gyroscopic effects
    • G01C19/56—Turn-sensitive devices using vibrating masses, e.g. vibratory angular rate sensors based on Coriolis forces
    • G01C19/5642—Turn-sensitive devices using vibrating masses, e.g. vibratory angular rate sensors based on Coriolis forces using vibrating bars or beams
    • G01C19/5649—Signal processing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01C—MEASURING DISTANCES, LEVELS OR BEARINGS; SURVEYING; NAVIGATION; GYROSCOPIC INSTRUMENTS; PHOTOGRAMMETRY OR VIDEOGRAMMETRY
    • G01C19/00—Gyroscopes; Turn-sensitive devices using vibrating masses; Turn-sensitive devices without moving masses; Measuring angular rate using gyroscopic effects
    • G01C19/56—Turn-sensitive devices using vibrating masses, e.g. vibratory angular rate sensors based on Coriolis forces
    • G01C19/5719—Turn-sensitive devices using vibrating masses, e.g. vibratory angular rate sensors based on Coriolis forces using planar vibrating masses driven in a translation vibration along an axis
    • G01C19/5733—Structural details or topology
    • G01C19/574—Structural details or topology the devices having two sensing masses in anti-phase motion
    • G01C19/5747—Structural details or topology the devices having two sensing masses in anti-phase motion each sensing mass being connected to a driving mass, e.g. driving frames

Definitions

  • TNF- ⁇ Tumor necrosis factor alpha
  • NF- ⁇ B nuclear factor ⁇ B
  • necroptosis The kinase activity of RIP1 is critically involved in mediating necroptosis, a caspase-independent pathway of necrotic cell death. Holler et al. Nat Immunol 2000; 1: 489-495 ; Degterev et al. Nat Chem Biol 2008; 4: 313-321 .
  • Necroptosis plays a role in various pathological forms of cell death, including ischemic brain injury, neurodegenerative diseases and viral infections. Dunai, et al., Dec 2011, Pathol. Oncol. Res.: POR 17 (4): 791-800 .
  • Necrostatin-1 (Nec-1), a small molecule inhibitor of RIP1 kinase activity, can block necroptosis. Degterev et al. Nat Chem Biol 2005; 1: 112-119 .
  • WO 2010075561 discloses heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-a) induced necroptosis.
  • the invention also provides the corresponding sulfonamides of all the generally and specifically disclosed amides, e.g. wherein S may be double bond to one or two O atoms, or a pharmaceutically acceptable salt, hydride or stereoisomer thereof, wherein the R moieties are as described herein, or a pharmaceutically acceptable salt, hydride or stereoisomer thereof.
  • the invention provides pharmaceutical compositions comprising the subject compounds, and methods of making and using the subject compounds, including methods of inhibiting cellular necrosis and/or human RIP1.
  • the compositions may comprise a pharmaceutically-acceptable excipient, be in effective, unit dosage form, and/or comprise another, different therapeutic agents for the targeted disease or condition.
  • the invention provides use of a compound of the invention or a composition of the invention for use in treating a person in need thereof with an effective amount of the subject compound or pharmaceutical composition.
  • amide inhibitors of cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1) of formula: wherein:
  • heterocyclics include isomers, such as iso-forms.
  • the compound is of formula I wherein:
  • the compound is of formula I wherein:
  • the subject compounds have a formula of Table 1.
  • the invention provides pharmaceutical compositions comprising a subject compound and a pharmaceutically-acceptable excipient, in unit dosage.
  • the invention provides pharmaceutical compositions comprising a subject compound and a pharmaceutically-acceptable excipient, in unit dosage, and a different therapeutic agent for a necrosis-associated disease or condition.
  • the invention provides compounds for use in methods of treating a necrosis-associated disease or condition, comprising administering an effective amount of a subject compound or composition to a patient in need thereof.
  • the method of treatment comprise the antecedent step of diagnosing the necrosis-associated disease or condition, or the subsequent step of detecting a resultant amelioration of the necrosis-associated disease or condition.
  • necrosis- including necroptosis
  • diseases or conditions are necrosis- (including necroptosis) associated and include neuro-degenerative disease of the central or peripheral nervous system, endotoxic/septic shock, terminal ileitis, myocarditis, arthritis, atherosclerosis, acute enteritis, ischemic necrosis, pathology resulting from renal failure or cell death, including retinal neuronal, cardiac muscle or immune cell death, such as chemo- or radiation-induced necrosis; liver disease, including drug-induced liver damage or toxicity, acute hepatitis, etc., pancreatic disease, including necrotizing pancreatitis, heart, mesenteric, retinal, hepatic or brain/cerebral ischemic injury, nephritis, ischemic injury during reperfusion or organ storage, head trauma, including traumatic brain injury, stroke, septic shock, coronary heart disease, cardiomyopathy, myocardial infarction, bone avascular necrosis, sickle cell disease, muscle
  • Exemplary applicable viruses are human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)5 human herpesviruses (HHV), herpes simplex viruses (HSV), human T-Cell leukemia viruses (HTLV)5 Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis viruses, adenovirus, parvoviruses, and human papillomaviruses.
  • Exemplary diseases caused by viral infection include, but are not limited to, chicken pox, Cytomegalovirus infections, genital herpes, Hepatitis B and C, influenza, and shingles.
  • Exemplary applicable bacteria include, but are not limited to Campylobacter jejuni, Enterobacter species, Enterococcus faecium, Enterococcus faecalis, Escherichia coli (e.g., E. coli O157:H7), Group A streptococci, Haemophilus influenzae, Helicobacter pylori, listeria, Mycobacterium tuberculosis, Pseudomonas aeruginosa, S. pneumoniae, Salmonella, Shigella, Staphylococcus aureus, and Staphylococcus epidermidis.
  • Campylobacter jejuni Enterobacter species
  • Enterococcus faecium Enterococcus faecalis
  • Escherichia coli e.g., E. coli O157:H7
  • Group A streptococci Haemophilus influenzae
  • Helicobacter pylori listeria
  • Exemplary diseases caused by bacterial infection include, but are not limited to, anthrax, cholera, diphtheria, foodborne illnesses, leprosy, meningitis, peptic ulcer disease, pneumonia, sepsis, tetanus, tuberculosis, typhoid fever, and urinary tract infection.
  • Exemplary applicable neurodegenerative diseases are Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, HIV-associated dementia, cerebral ischemia, amyotropic lateral sclerosis, multiple sclerosis, Lewy body disease, Menke's disease, Wilson's disease, Creutzfeldt-Jakob disease, and Fahr disease.
  • Exemplary applicable muscular dystrophies or related diseases are Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease.
  • Muscle wasting can be associated with cancer, AIDS, congestive heart failure, and chronic obstructive pulmonary disease, as well as include necrotizing myopathy of intensive care.
  • the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
  • genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.
  • heteroatom as used herein generally means any atom other than carbon or hydrogen.
  • Preferred heteroatoms include oxygen (O), phosphorus (P), sulfur (S), nitrogen (N), and halogens, and preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 -CH 2 -CH 2 -CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds.
  • a heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1-(1,2,5,6-tetrahydropyrid-yl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo and “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1), where m' is the total number of carbon atoms in the alkyl group.
  • halo(C1-C4)alkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group).
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
  • perhalo(C1-C4)alkyl is meant to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl and the like.
  • acyl refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalene.
  • heteroaryl refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naph
  • R', R" and R' each independently refer to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ).
  • the aryl group When the aryl group is 1,2,3,4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7)spirocycloalkyl group.
  • the (C3-C7)spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl".
  • an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention.
  • an aryl or heteroaryl group will be unsubstituted or monosubstituted.
  • an aryl or heteroaryl group will be unsubstituted.
  • Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR', - OC(O)R', -NR'R", -SR', -R', -CN, -NO 2 ,-CO 2 R', -CONR'R", -C(O)R',-OC(O)NR'R", - NR"C(O)R', -S(O)R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, -N 3 , -CH(Ph) 2 , perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, where R' and R" are as defined above.
  • substituents are selected from: halogen, -OR', -OC(O)R', -NR'R", -R', -CN, -NO 2 ,-CO 2 R', -CONR'R", - NR"C(O)R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4) alkyl.
  • the substituent -CO 2 H includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press: New York, 1996; p. 203 .
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 )q-U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 )s-X-(CH 2 )t- -, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, - S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (C1-C6)alkyl.
  • substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.
  • applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, 0-3 heteroatom C1-C6 alkyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkenyl, substituted or unsubstituted, 0-3 heteroatom C2-C6 alkynyl, or substituted or unsubstituted, 0-3 heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.
  • applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF3).
  • OCF3 trifluoromethyl or trifluromethyl ether
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phospho
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
  • Additional examples include peptidyl derivatives of a compound of the invention.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein).
  • compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, losenges or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • compositions may be administered separately, jointly, or combined in a single dosage unit.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application.
  • unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient.
  • microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10 or 100 ug/kg to about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
  • a dosage regimen of the compoundss can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
  • the titled compound 2 was prepared in 77% yield from 2-phenylazetidine (50mg) and 2,2-dimethylbutanoyl chloride(55mg) according to the procedure outlined for compound1.
  • the titled compound 3 was prepared in 77% yield from (S)-2-phenylazetidine(50mg) and 2,2-dimethylbutanoyl chloride(55mg) according to the procedure outlined for compound 1.
  • the titled compound 4 was prepared in 46% yield from 2-phenylpyrrolidine (50mg) and 2,2-dimethylbutanoyl chloride (55mg) according to the procedure outlined for compound 1.
  • the titled compound 5 was prepared in 46% yield from 2-cyclohexylpyrrolidine (70mg) and 2,2-dimethylbutanoyl chloride(73mg) according to the procedure outlined for compound 1.
  • 1 HNMR(CDCl 3 , 400MHz): ⁇ 4.13-4.18 (m, 1 H), 3.74-3.80 (m, 1 H), 3.27-3.33 (m, 1 H), 1.87-2.00 (m, 5 H), 1.65-1.82 (m, 6 H), 1.53-1.60 (m, 2 H), 1.22 (s, 6 H), 0.92-1.18 (m, 4 H), 0.87 (t, 3 H, J 7.6 Hz).
  • the titled compound 6 was prepared in 46% yield from2-phenyloxazolidine (80mg) and 2,2-dimethylbutanoyl chloride(108mg) according to the procedure outlined for compound1.
  • the titled compound 7 was prepared in 46% yield from(S)-4-phenyloxazolidine (57mg) and 2,2-dimethylbutanoyl chloride (102mg) according to the procedure outlined for compound 1.
  • the titled compound 8 was prepared in 46% yield from (R)-4-phenyloxazolidine (80mg) and 2,2-dimethylbutanoyl chloride (86mg) according to the procedure outlined for compound 1.
  • the titled compound 9 was prepared in 66% yield from 2-(3-fluorophenyl)pyrrolidine (95mg) and 2,2-dimethylbutanoyl chloride(93mg) according to the procedure outlined for compound 1.
  • the titled compound 10 was prepared in 66% yield from 2-(2,3,5-trifluorophenyl)pyrrolidine (50mg) and 2,2-dimethylbutanoyl chloride (34mg) according to the procedure outlined for compound 1.
  • 1 HNMR(CDCl 3 , 400MHz): ⁇ 6.66-6.71 (m, 1 H), 6.44-6.46 (m, 1 H), 5.43-5.46 (m, 1 H), 3.79-3.86 (m, 2 H), 2.21-2.26 (m, 1 H), 1.90-1.98 (m, 2 H), 1.69-1.77 (m, 1 H), 1.61-1.68 (m, 2 H), 1.26 (s, 3 H), 1.23 (s, 3 H), 0.89 (t, 3 H, J 7.6 Hz).
  • the titled compound 11 was prepared in 53% yield from 2-phenylpiperidine (50mg) and 2,2-dimethylbutanoyl chloride(50mg) according to the procedure outlined for compound 1.
  • the titled compound 12 was prepared 20% yield from 3-phenylmorpholine (25mg) and 2,2-dimethylbutanoyl chloride(23mg) according to the procedure outlined for compound 1.
  • (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-phenylpyrrolidine(185mg) and trimethylamine (0.18ml) were dissolved in in 2 mL of dry dichloromethane.
  • the mixture was cooled to 0°C and 2,2-dimethylbutanoyl chloride (134mg) was added, then allowed to warm to room temperature and stirred for 16h.
  • the mixture was diluted with dichloromethane and water.
  • the aqueous layer was extracted with dichloromethane.
  • the organic layers were combined and concentrated.
  • the titled compound 14 was prepared in 46% yield from 3,3-difluoro-2-phenylazetidine (25mg) and 2,2-dimethylbutanoyl chloride (40mg) according to the procedure outlined for compound 1.
  • tert-butyl 4-(2,2-dimethylbutanoyl)-3-phenylpiperazine-1-carboxylate (0.8g) was dissolved in 3ml of EtOAc, then 4N HCl in EtOAc (10ml) was added. The mixture was stirred at room temperature for 3h. After removing solvent, the residue was washed with petroleum ether to get compound 150(0.45g, 68%) as HCl salt, which was used for next step without further purification.
  • the titled compound 18 was prepared in 52% yield from compound 17 (20mg) and acetyl chloride (6.4mg) according to the procedure outlined for compound 1.
  • 1 HNMR(CDCl 3 ,400MHz): ⁇ 1H-NMR (CDCl3) ⁇ 7.27-7.35 (m, 5 H), 5.75-5.77(m, 1 H), 4.27-4.30 (m, 1 H), 4.11-4.21 (m, 2 H), 3.58-3.64 (m, 2 H), 3.23-3.30 (m, 1 H), 2.03 (s, 3 H), 1.61-1.66 (m, 2 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 0.95 (t, 3 H, J 8.0 Hz).
  • the titled compound 19 was prepared in 90% yield from tert-butyl3-phenylpiperazine-1-carboxylate (500mg) and 2,2-dimethylbutanoyl chloride (282mg) according to the procedure outlined for compound 1.
  • the titled compound 20 was prepared in 46% yield from 5-phenyl-4,5-dihydro-1H-pyrazole (60mg) and 2,2-dimethylbutanoyl chloride (56mg) according to the procedure outlined for compound1.
  • n-BuLi (2.4 M in THF, 0.214 mL, 0.51 mmol) was added slowly to a solution of (R)-4-phenyloxazolidin-2-one (80 mg, 0.49 mmoL) in 2 mL of THF at 0°C under nitrogen, which was stirred at 0°C for 50 min. Then 2,2-dimethylbutanoyl chloride (78.9 mg, 0.59 mmol) was added slowly to the solution at 0°C. The mixture was allowed to stir at room temperature for 3.5 h and quenched with saturated aqueous solution of NH 4 Cl. The aqueous layer were extracted with EtOAc (5 mL x 3).
  • Compound 28 was prepared in 25% yield from 4-(3-nitrophenyl)azetidin-2-one (10mg) (prepared form 1-nitro-3-vinylbenzene(200mg)and chlorosulfonyl isocyanate (116ul) according to the procedure outlined for compound 170) and 2,2-dimethylbutanoyl chloride(179mg) according to the procedure outlined for compound 25.
  • the titled compound 29 was prepared in 38% yield from 5-phenylpyrrolidin-2-one (50mg) and 2,2-dimethylbutanoyl chloride(50mg) according to the procedure outlined for compound 1.
  • the titled compound 31 was prepared from (R)-3-(2,2-dimethylbutanoyl)-1-methyl-4-phenylimidazolidin-2-one (50mg) and 2,2-dimethylbutanoyl chloride (45mg) according to the procedure outlined for compound 1.
  • the titled compound 32 was prepared in 60% yield from 3,3-difluoro-4-phenylazetidin-2-one (30mg) and 2,2-dimethylbutanoyl chloride (44mg) according to the procedure outlined for compound 164.
  • the titled compound 33 was prepared in 25% yield from phenylpyrazolidin-3-one (50mg) and 2,2-dimethylbutanoyl chloride(50mg) according to the procedure outlined for compound 1.
  • the titled compound 36 was prepared in 32% yield from 1-(trifluoromethyl)cyclobutanecarboxylic acid (20mg) and 2-(3-fluorophenyl)pyrrolidine (19.6mg) according to the procedure outlined for compound 35.
  • the titled compound 37 was prepared in 46% yield from 2-(3-fluorophenyl)pyrrolidine (60mg) and adamantane-1-carbonyl chloride (81mg) according to the procedure outlined for compound 1.
  • the titled compound 38 was prepared in 34% yield from (S)-4-phenylazetidin-2-one (100mg) and 2,2-dimethylbut-3-enoyl chloride (107mg) according to the procedure outlined for compound 1.
  • the titled compound 39 was prepared in 60% yield from (R)-4-phenyloxazolidin-2-one (80mg) and acetyl chloride (46mg) according to the procedure outlined for compound 1.
  • the titled compound 42 was prepared in 34% yield from (S)-4-phenylazetidin-2-one (50mg) and prop ane-2- sulfonyl chloride (58mg) according to the procedure outlined for compound 23.
  • the titled compound 43 was prepared in 33% yield from(S)-4-phenylazetidin-2-one (50mg) and ethanesulfonyl chloride(52.5mg) according to the procedure outlined for compound 23.
  • Compound 44 was prepared in 1.3% yield from 4-(3-azidophenyl)azetidin-2-one (50mg) (prepared according to the procedure outlined for compound 25) and 2,2-dimethylbut-3-ynoyl chloride(69mg) according to the procedure outlined for compound 24.
  • the titled compound 47 was prepared in 32% yield from (S)-4-phenylazetidin-2-one (50mg) and adamantane-2-carbonyl chloride (81mg) according to the procedure outlined for compound 24.
  • the titled compound 50 was prepared in 9.7% yield from(S)-4-phenylazetidin-2-one (15 mg), (bromomethyl)cyclopropane (15 mg) and NaH (4.5 mg, 60% in material oil) according to the procedure outlined for compound 48.
  • the titled compound 52 was prepared in 46% yield from (R)-4-phenyloxazolidin-2-one (80mg) and 3-bromoprop-1-yne (116mg) according to the procedure outlined for compound 51.
  • (2R,3S)-2-phenyl-1-tosylpyrrolidin-3-ol was prepared according to methods previously described ( US2009/0012120A1 ) (35 mg) and phenol(31 mg) were added in 4 mL of HBr(48%, w/w). The mixture was strried at 100°C for 12h and then cooled to room temperature, extracted with ether(2mL) and the ether layer was discarded. The aqueous was freeze-dried to give (2R,3S)-2-phenylpyrrolidin-3-ol(30 mg) without further purification.
  • the above intermediate was dissolved in dry DMSO (2 mL) and sodium acetate trihydrate (12 mg) was added. The mixture was stirred at 100°C for 60h and 4mL of water was added . The aqueous layers were extracted with DCM (15 mL x 3) and the organic layers was combined, washed with brine, dried with Na 2 SO 4 and evaporated to dryness. The residue was used for next step without further purification.
  • the above intermediate (15 mg) was dissolved in THF(1 mL) and MeOH(0.2 mL) and 0.01 mL IN NaOH was added. The mixture was stirred at 0°C for 1 h and neutralized with IN HCl.
  • Scheme1 reagent and conditions: (a) Na/THF, -78°C (b) 3,3-difluoro-2,2-dimethyl butanoic acid, EDCI, DIEA, DMF, rt.
  • Scheme 2 reagent and conditions: (a) Pd/C, H 2 (b) 3,3-difluoro-2,2-dimethylbutanoyl chloride, NaH, THF.
  • Scheme 4 reagent and conditions: (a) TFA/DCM (b) 3,3-difluoro-2,2-dimethylbutanoyl chloride, Et 3 N, DCM.
  • Scheme 5 reagent and conditions: (a) K 2 CO 3 , thiophenol, DMF (b) 3,3-difluoro-2,2 dimethylbutanoyl chloride , Et 3 N, DCM.
  • Recombinant full-length RIPK1 protein with N-terminal GST-tag (Cat#R07-34G) was purchased from SignalChem.
  • the ADP-GloTM kinase assay kit (Cat#V9102) was from Promega.
  • MBP (cat# M2295) protein and all the other chemicals were from Sigma.
  • the 384-well assay plates (Cat# 3674, white, opaque) were purchased from Corning.
  • the RIPK1 kinase assay was performed in white 384-well plate.
  • the assay buffer contained 25mM HEPES (pH7.2), 20 mM MgCl2, 12.5 mM MnC12, 5 mM EGTA, 2 mM EDTA, 12.5 mM ⁇ -glycerol phosphate and 2 mM DTT.
  • RIPK1 was first incubated with compounds or DMSO control for 15 min, then ATP/MBP substrate mixture was added to initiate the reaction. The final concentration of RIPK1 was 161 nM, while the final concentration of ATP was 50 uM , and MBP 20uM.
  • ADP-Glo reagent and detection solution were added following the technical manual of ADP-GloTM kinase assay kit (Promega). The luminescence was measured on PerkinElmer Enspire. The data was analyzed using Graphpad Prism (GraphPad Software; www.graphpad.com). The curves were fitted using a non-linear regression model with a sigmoidal dose response.
  • HT-29 cells were cultured in McCoy's 5A culture medium (Invitrogen). On day one, HT-29 cells were plated in 96-well assay plates at density of 2,500-3,500 cells per well. On day two, necrosis were induced by adding 20ng/ml TNF- ⁇ (T), 100nM Smac mimetic (S), and 20mM z-VAD (Z). At the same time, 10mM compound from a chemical library of ⁇ 200,000 compounds was delivered into each well. After 24 hrs treatment, cell viability was determined by measuring ATP level using the CellTiter-Glo Luminescent Cell Viability Assay kit.
  • Luminescence was recorded with a PerkinElmer EnSpire Multimode Plate Reader. Survived cells were normalized to those cells treated with DMSO. Nec-1 was used as a positive control for screening necrosis inhibitors. Data are represented as mean ⁇ standard deviation of duplicates

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Claims (13)

  1. Amidverbindung gemäß der Formel:
    Figure imgb0225
     wobei:
    R1 ein
    (a) substituiertes oder unsubstituiertes Phenyl;
    (b) substituiertes oder unsubstituiertes 2-, 3- oder 4-Pyridin;
    (c) substituiertes oder unsubstituiertes Naphthyl or 3-Azanaphthyl;
    (d) substituiertes oder unsubstituiertes 0-3 Heteroatom-Cyclohexyl oder - Cyclopentyl; oder
    (e) substituiertes oder unsubstituiertes 0-3 Heteroatom-Cyclopentene oder - Cyclopentadiene; ist;
    R2 ein substituiertes oder unsubstituiertes Aziridin, Azetidin, Pyrrolidin, Piperidin, Oxaziridin, Oxazetidin, Oxazolidin, Oxazinan, Thiaziridin, Thiazetidin, Thiazolidin, Thiazinan, Diaziridin, Diazetidin, Diazolidin (Pyrazolidin) oder Diazinane; ist; oder
    R2 ein substituiertes oder unsubstituiertes Pyrrol, Dihydropyrrol, Pyridin, Dihydropyridin, Tetrahydropyridin, Azole, Pyrimidine, Oxazin, Thiazin, Triazin, Ozadiazin, Thiadiazin; ist; und
    R3 ein 1,1-Dimethylpropyl, 1,1-Dimethylprop-2-enyl, oder 1,1-Dimethylprop-2-ynyl, jeweils optional fluoriert mit 1-4 F Atomen ist,
    wobei jedes Heteroatom unabhängig voneinander Sauerstoff, Phosphor, Schwefel oder Stickstoff; oder
    ein entsprechendes Sulfonamid der Amidverbindung, oder
    ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamides ist.
  2. Verbindung gemäß Anspruch 1 wobei:
    R1 ein substituiertes oder unsubstituiertes: Phenyl, Cyclohexyl, Furan, Thiophene oder Azole ist;
    R2 ein substituiertes oder unsubstituiertes: Aziridin, Azetidin, Pyrrolidin, Piperidin, Oxazolidin, Oxazinan; Diazolidin, Diazinan, Pyrrol, Dihydropyrrol, Dihydropyridin, oder Tetrahydropyridin ist.
  3. Verbindung gemäß einem der Ansprüche 1-2 wobei:
    R1 ein substituiertes oder unsubstituiertes Phenyl oder Cyclohexyl; oder ein entsprechendes Sulfonamid der Amidverbindung, oder ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamides ist.
  4. Verbindung gemäß einem der Ansprüche 1-3 wobei:
    R2 ein unsubstituiertes: Azetidin, Pyrrolidin, Piperidin, Oxazolidin, Diazolidin, Diazinan; oder ein entsprechendes Sulfonamid der Amidverbindung, oder ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamid ist.
  5. Verbindung gemäß einem der Ansprüche 1-4, wobei:
    R1 ein unsubstituiertes Phenyl oder ein entsprechendes Sulfonamid der Amidverbindung, oder ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamid ist.
  6. Verbindung gemäß einem der Ansprüche 1-5 wobei:
    R2 ein unsubstituiertes: Azetidin, Pyrrolidin, Piperidin, Oxazolidin, Diazolidin, Diazinan; oder ein entsprechendes Sulfonamid der Amidverbindung, oder ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamid ist.
  7. Verbindung gemäß einem der Ansprüche 1-6 wobei:
    R3 1,1-Dimethylpropyl; oder ein entsprechendes Sulfonamid der Amidverbindung oder ein pharmazeutisch akzeptables Salz, Hydrat oder Stereoisomer der Verbindung oder des entsprechenden Sulfonamid ist.
  8. Verbindung gemäß Anspruch 1 mit einer Formel nach Tabelle 1:
    Figure imgb0226
    Figure imgb0227
    Figure imgb0228
         1 2 3
    Figure imgb0229
    Figure imgb0230
    Figure imgb0231
         4 5 6
    Figure imgb0232
    Figure imgb0233
    Figure imgb0234
         7 8 9
    Figure imgb0235
    Figure imgb0236
    Figure imgb0237
         10 11 12
    Figure imgb0238
    Figure imgb0239
    Figure imgb0240
         13 14 15
    Figure imgb0241
    Figure imgb0242
    Figure imgb0243
         16 17 18
    Figure imgb0244
    Figure imgb0245
         21 19
    Figure imgb0246
    Figure imgb0247
    Figure imgb0248
         22 23 24
    Figure imgb0249
    Figure imgb0250
    Figure imgb0251
         25 26 27
    Figure imgb0252
    Figure imgb0253
    Figure imgb0254
         28 29 30
    Figure imgb0255
    Figure imgb0256
    Figure imgb0257
         32 33
    Figure imgb0258
    Figure imgb0259
         46
    Figure imgb0260
    Figure imgb0261
         53 54
    Figure imgb0262
    Figure imgb0263
    Figure imgb0264
         55 56 57
    Figure imgb0265
    Figure imgb0266
    Figure imgb0267
         58 59 60
    Figure imgb0268
    Figure imgb0269
    Figure imgb0270
         61 62 63
    Figure imgb0271
    Figure imgb0272
    Figure imgb0273
         64 65 66
    Figure imgb0274
    Figure imgb0275
    Figure imgb0276
         67 68 69
    Figure imgb0277
    Figure imgb0278
    Figure imgb0279
         70 71 72
    Figure imgb0280
    Figure imgb0281
    Figure imgb0282
         73 74 75
    Figure imgb0283
         78
    Figure imgb0284
    Figure imgb0285
    Figure imgb0286
         S1 S2 3S
    Figure imgb0287
    Figure imgb0288
         S4 S5
    Figure imgb0289
         S10
    Figure imgb0290
    Figure imgb0291
    Figure imgb0292
         S13 S14 S15
    Figure imgb0293
    Figure imgb0294
         S16 S17.
  9. Verbindung gemäß Anspruch 1 gemäß der Formel:
    Figure imgb0295
  10. Verbindung gemäß Anspruch 1 gemäß der Formel
    Figure imgb0296
  11. Pharmazeutische Zusammensetzung enthaltend eine Verbindung gemäß einem der Ansprüche 1-10 und ein pharmazeutisch akzeptabler Hilfsstoff, in Einheiten Formulierung.
  12. Pharmazeutische Zusammensetzung enthaltend eine Verbindung gemäß einem der Ansprüche 1-10 und ein pharmazeutisch akzeptabler Hilfsstoff, in Einheiten Formulierung, und ein anderer therapeutischer Stoff für eine Nekrose-assoziierte Erkrankung oder Zustand.
  13. Verbindung gemäß einem der Ansprüche 1-10 oder Zusammensetzung gemäß Ansprüchen 11 oder 12 zur Verwendung in der Behandlung einer Nekrose-assoziierten Erkrankung oder Zustand, umfassend verabreichen einer effektiven Menge der Verbindung oder der Zusammensetzung an einen Patienten, der dies benötigt.
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